Angiogenesis is critical for a number of physiological and pathophysiological processes and angiogenesis inhibitors are now being evaluated in clinical trials. Recently, we discovered the angiogenesis inhibitors angiostatin, endostatin, and antiangiogenic antithrombin (aaAT) by studying the inhibition of tumor growth by tumor mass. All three are derived from proteolysis of endogenous proteins. In vivo, these agents have been used to regress a wide variety of malignant tumors and can induce a type of tumor dormancy sustained by a dynamic equilibrium between tumor cell apoptosis and proliferation and a virtual complete blockade of angiogenesis. However, preclinical studies demonstrate a significant delay in the onset of activity after initiation of antiangiogenic therapy and tumors often progress before responding to treatment even when high doses are administered. Further, microscopic residual disease persists in all animals and there is emerging evidence of heterogeneity of the endothelium suggesting that angiogenesis inhibitors may have differential activity in different capillary beds. When taken together, these findings suggest that the use of antiangiogenic agents as monotherapy will not be adequate for most patients with advanced cancer. The goal of this project is to develop a rational basis for the integration of antiangiogenic therapy with radiation therapy. The first specific aim is to use preclinical models of cancer to optimize the combination of antiangiogenic agents with radiation therapy. The hypothesis is that the limitations of antiangiogenic agents and conventional modalities will be diminished when they are combined and a synergistic effect will result. The second specific aim is to develop and validate surrogates to monitor the effects of antiangiogenic therapy when given in combination with radiation therapy. Useful surrogates that predict for early tumor response are of critical importance for the incorporation of antiangiogenic therapy into clinical practice. The results obtained in these studies will have direct relevance to the planning of clinical trials for cancer.